This competitive renewal examines further the influence of dopamine beta-hydroxylase (DBH) enzyme activity on the efficacy of the novel pharmacotherapy, disulfiram, for treating cocaine dependence in opioid- and cocaine-dependent patients maintained on methadone. Cocaine use remains epidemic among most opioid maintenance programs and pharmacological therapeutic strategies specifically aimed at cocaine's dopaminergic actions have shown little efficacy in unselected populations. In our previous trial, we have shown that DBH activity influences response to disulfiram at lower doses (0, 62.5, 125, or 250 mg/day), such that, disulfiram at 62.5 and 125 mg/day increases and disulfiram at 250 mg/day decreases, respectively, cocaine use relative to placebo in cocaine-dependent, methadone-stabilized patients with low DBH activity. Disulfiram produced no differential effects on cocaine use in those with normal DBH activity. Thus, our aim is to examine the influence of DBH activity on the efficacy of disulfiram at higher doses for treating 160 methadone-maintained cocaine abusers in a 14-wk, double blind, randomized clinical trial. Because DpH activity is under strong genetic control, participants will be stratified on genotype at the dopamine beta- hydroxylase (DBH) locus to ensure equal proportions of subjects across treatment groups. Methadone induction, genotyping, and assessment of baseline cocaine use will occur during weeks 1-2. Then participants will continue on methadone, be stratified by genotype, etc., and be randomly assigned to receive one of the following doses of disulfiram for the next 12 weeks: 0, 250, 375, 500 mg/day. At the end the study, participants will no longer receive disulfiram and either transfer to a regular methadone program or undergo detoxification from methadone over a 4- to 6-wk period. In order to enhance outcome, all participants receive weekly 1-hour psychotherapy (Cognitive Behavioral Treatment) with experienced clinicians specifically trained to deliver the therapy and who will receive ongoing supervision. The primary outcome will be the influence of genotype at the DBH locus and/or DBpH enzyme activity on reduction cocaine use, as assessed by thrice-weekly urinalyses. Secondary outcomes will include retention, reductions in other illicit drug and alcohol use, disulfiram side-effects profile, and improvements in psychosocial functioning. The prognostic relevance of other factors (e.g., sex, discounting behavior) will also be examined. [unreadable] [unreadable] [unreadable]